In humans, as in mice, chronic exposure to ultraviolet radiation B (UVB, 290-320 nm) impairs host immune responses in addition to inducing mutant cells. Tumors will occur only when there are mutant cells in an immune suppressive environment. In fact, organ transplant recipients who are treated with immunosuppressive medications have a greatly increased risk (up to 100 times) of skin cancers and the tumors that do develop behave more aggressively. It has been known that UVB induced DNA damage is a trigger for immune tolerance. Cell senescence is a protective mechanism to prevent transformation and growth of cells with DNA damage. Senescent cells can produce many inflammatory mediators, a phenomenon called senescence associated secretory phenotype (SASP). SASP recruits and activates immune cells to eliminate DNA damaged cells, which is a critical mechanism of immune surveillance. However, SASP also has roles in immunosuppression and tumor promotion. It is known that UVB induces cell senescence and SASP. However, it is not known whether SASP is a mechanism for UVB induced tolerance. Our studies show that depletion of senescent cells diminishes UVB induced SASP and inhibits tolerance. The result reveals a previously unrecognized mechanism for UVB induced tolerance. Further, we have found that CD11b+/PD-L1+ cells are significantly increased by UVB whereas they are reduced by depletion of senescent cells. Importantly, treatment with anti-PD-L1 antibodies inhibits UVB induced tolerance. To our best knowledge, this is the first evidence that PD-1/PD-L1 checkpoint inhibitor has a role in UVB induced tolerance. Our hypothesis is that UVB induced cell senescence and SASP are a novel mechanism for UVB induced tolerogenic antigen presenting cells (APC), Treg cells, and immune tolerance. Aim 1 will examine mechanisms by which depletion of senescent cells inhibits UVB induced tolerance and immune suppressive environments in skin. We will examine whether depletion of senescent cells inhibits Treg cells and enhances effector T cells. Further studies will determine whether SASP mediated recruitment and stimulation of myeloid cells is a mechanism for UVB induced tolerogenic APC and tolerance. We will also examine whether UVB induced SASP is associated with tolerance in humans. Aim 2 will determine a novel role of IL-17 in UVB induced SASP and carcinogenesis. We will determine whether IL-17 is a component and an upstream regulator of UVB induced SASP and examine molecular mechanisms by which IL-17 regulates SASP. Further studies will examine whether blockade of IL-17 diminishes the susceptibility of mice to photocarcinogenesis. Aim 3 will determine whether CD11b+/PD-L1+ cells are specific tolerogenic APC for the induction of Treg cells and tolerance and whether blockade of PD- 1/PD-L1 reverses established immune tolerance in UVB-tolerized mice. Further studies will examine whether blockade of PD-1/PD-L1 inhibits photocarcinogenesis and whether a combination with neutralizing IL-17 enhances the efficacy of immunotherapy for UVB induced skin tumors.